U.S. Pat. No. 4,835,152 discloses that the compound 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiaz epine possesses central nervous system effects.
European patent application publication number EP-A1-0492485 discloses 2,3-benzodiazepine derivatives and other dihydro-2,3-benzodiazepine derivatives also having central nervous system effects, in particular muscle-relaxant and anticonvulsive activity. The compounds disclosed in EP-A1-0492485 are represented by the general formula. ##STR1## wherein R.sup.a stands for a C.sub.1-6 aliphatic acyl group, optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group, or by one or more halogen(s); or R.sup.a is a benzoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group; or R.sup.a is absent when a double bond exists between the N(3) and C(4) atoms;
R.sup.1 means hydrogen; or R.sup.1 is absent when a double bond exists between the N(3) and C(4) atoms; PA1 R.sup.2 means a C.sub.1-3 alkyl group; or PA1 R.sup.1 and R.sup.2 together stand for a methylene group and no double bond is present between the N(3) and C(4) atoms; PA1 R.sup.3 means hydrogen or a C.sub.1-4 aliphatic acyl group; PA1 R.sup.4 represents hydrogen; a C.sub.1-6 aliphatic acyl group optionally substituted by a methoxy, cyano, carboxyl, amino, C.sub.1-4 alkylamino, di(C.sub.1-4 alkyl)amino, pyrrolidino, phthalimido or phenyl group or by one or more halogen(s); as well as a benzoyl, palmitoyl, cyclopropanecarbonyl, C.sub.1-5 alkylcarbamoyl or phenylcarbamoyl group; and the dotted lines represent valence bonds optionally being present, with the proviso that no double bond exists between the N(3) and C(4) atoms when both R.sup.3 and R.sup.4 stand for hydrogen. PA1 X is hydrogen, C.sub.1 -C.sub.10 alkyl, acyl, aryl, or carboxyl, or a substituted derivative thereof. PA1 X is hydrogen, C.sub.1 -C.sub.10 alkyl, acyl, aryl, carboxyl or a substituted derivative thereof, or a protecting group, or a pharmaceutically acceptable salt thereof, said process comprising cyclising a compound having the general formula ##STR5## wherein Z represents a leaving atom or group, to afford a compound having the general formula I, whereafter, if desired, converting the compound of formula I into another compound of formula I and/or forming a pharmaceutically acceptable salt. PA1 (a) reducing a p-nitrophenyl group to afford a p-aminophenyl group, or PA1 (b) deprotecting a p-(protected amino)phenyl group to afford a p-aminophenyl group. PA1 (a) reducing a p-nitrophenyl group to afford a p-aminophenyl group; PA1 (b) deprotecting a p-(protected amino)phenyl group to afford a p-aminophenyl group; PA1 (c) removing a protecting group represented by X to afford a compound of formula I in which X is hydrogen; and/or PA1 (d) acylating a compound of formula I in which X is hydrogen to afford a compound of formula I in which X is formyl, acetyl, propionyl or N-methylcarbamoyl; and, if desired, forming a pharmaceutically acceptable salt. PA1 X is hydrogen, C.sub.1 -C.sub.10 alkyl, acyl, aryl, carboxyl, or a substituted derivative thereof; said process comprising the steps of:
International patent application publication number WO 92/11262 also discloses certain dihydro-2,3-benzodiazepine derivates having central nervous system effects, in particular antidepressive and/or antiparkinsonian action. The compounds may be represented by general formula (A) above in which R.sup.1 represents hydrogen, R.sup.2 represents methyl, R.sup.a represents hydrogen or a C.sub.1-4 alkyl group optionally substituted by a carboxyl or C.sub.2-5 alkoxycarbonyl group, R.sup.3 represents hydrogen and R.sup.4 represents an aliphatic C.sub.1-6 acyl, benzoyl or phenylacetyl group.
It is now known that the compounds disclosed in U.S. Pat. No. 4,853,152, EP-A1-0492485 and WO 92/11262 are potent antagonists of the AMPA (.alpha.-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) class of receptors in the mammalian central nervous system. They have potentially widespread applications as neuroprotective agents, particularly as anticonvulsants. Thus they may be useful in the treatment of epilepsy, cerebral ischemia, brain and spinal trauma, status seizures, Parkinson's disease and amyotrophic lateral sclerosis.
The dihydro-2,3-benzodiazepines disclosed in U.S. Pat. No. 4,835,152, EP-A1-0492485 and WO92/11262 possess a centre of asymmetry at position 4. It is now known that the (R) enantiomers, for example, (R)-7-acetyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1,3-dioxolo4,5-h! 2,3!benzodiazepine (also known as (R)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H- 2,3-benzodiazepine), are more potent than the (S) enantiomers.
U.S. Pat. No. 4,835,152, EP-A1-0492485 and WO 92/11262 disclose synthetic routes for preparing the dihydro-2,3-benzodiazepines. In these routes, the dihydro-2,3-benzodiazepine ring is formed by selectively reducing a corresponding 2,3-benzodiazepine compound using an inorganic or organic-inorganic and/or complex metal hydride, such as sodium borohydride, followed if desired by separating optically active forms.
An elegant, stereoselective synthesis has now been found for preparing the (R) enantiomers of the dihydro-2,3-benzodiazepines disclosed in U.S. Pat. No. 4,835,152, EP-A1-0492485, WO 92/11262 and of certain other dihydro-2,3-benzodiazepines.